Scientists at Karolinska Institutet in Sweden have discovered why a certain cancer treatment sometimes fails — and how to fix it. Their findings, published in the journal Nature Communications, could help doctors predict which patients will benefit from immunotherapy and open the door to new combination treatments for cancer.
The research focused on macrophages, a type of immune cell that lives inside tumors. These cells can either help the body fight cancer or actually protect the tumor, depending on how they are programmed. Immunotherapy aims to flip these cells from supporters of cancer into cancer fighters. But the treatment does not work for everyone, and researchers wanted to understand why.
The team, led by Professor Mikael Karlsson at Karolinska Institutet's Department of Microbiology, Tumor and Cell Biology, found that the therapy only works when macrophages have functional TLR9 receptors. These receptors act like tiny sensors inside cells, helping them respond to the treatment. When the researchers removed these receptors in mouse models, the immunotherapy had no effect on tumor growth. The macrophages simply stayed in their cancer-protecting mode.
"Without these receptors, the treatment is ineffective," Professor Karlsson said. "This knowledge makes it possible to investigate whether tumors are sensitive to this type of treatment, and it also paves the way for new combination therapies."
But the news is not just about understanding failure — it is also about making success more likely. When researchers combined the immunotherapy with substances that activate TLR9, the treatment became more powerful. The effect on tumors increased, suggesting that doctors could potentially boost existing therapies by adding TLR9-activating drugs.
The team also analyzed human tumor samples and found links between the treatment target MARCO and TLR9 in breast cancer and other cancers. This suggests the discovery may apply to real patients, not just mice.
The study was a collaboration with the University of Toronto, Rockefeller University, and clinical departments at the university hospital. Researchers used mouse models to investigate how different immunotherapies respond to the presence or absence of TLR9 receptors.
Looking ahead, the researchers plan to use these findings to develop and test new treatment strategies, including combinations of immunotherapies that could help patients whose tumors are currently difficult to treat. The goal is to eventually help more people benefit from cancer immunotherapy.